The present invention relates to xe2x80x9ca process for the preparation of pharmacologically active xcex1-asarone from toxic xcex2-asarone rich Acorus calamus oil via intermediate 2,4,5-trimethoxyphenylpropane of the formula I (a dihydro product of toxic xcex2-asarone) which is obtained via hydrogenation of commercially available Acorus calamus oil rich in xcex2-asarone containing xcex1 and xcex3 isomer), undergoes dehydrogenation and/or oxidation in a single step by just varying reaction time, temperature, solvent (anhydrous) and amount of dichlorodicyanobenzoquinone (DDQ) with or without a solid support such as silica gel, alumina and the like towards formation of xcex1-asarone (trans-2,4,5-trimethoxyphenyl-1-propene), a well known pharmacolocally active phenylpropanoid, and trans-2,4,5-trimethoxycinnamaldehyde as a side product. However, above dehydrogenation process when conducted in aqueous solvent provides 1-(2,4,5-trimethoxy)phenyl-1-propanone which upon reduction with sodium borohydride into 1-(2,4,5-trimethoxy)phenyl-1-hydroxypropane followed by acidic dehydration affords xcex1-asarone exclusively. Moreover, it is worthwhile to mention that 1-(2,4,5-trimethoxy)phenyl-1-propanone (isoacoramone) and 2,4,5-trimethoxycinnamaldehyde are found as phenylpropanoids present in traces in some of the aromatic and medicinal plants. Overall, the aim of this invention is to utilize internationally banned, but widely available toxic xcex2-asarone as a simple and economical starting material for the preparation of a potential hypolipidemic and antiplatelet active xcex1-asarone via combination of two simple industrially attractive processes i.e. hydrogenation and dehydrogenation/oxidation in which formation of the unexpected 2,4,5-trimethoxycinnamaldehyde is discovered as a side product during preparation of xcex1-asarone. In the present invention, we have disclosed a simple and economical process that is capable of converting toxic xcex2-asarone into pharmacological active xcex1-asarone in high yield without contamination of its other isomers i.e. and/or xcex3-asarone. 
Although the plant derived products have found widespread applications in the field of essential oils, colours and dyes, cosmetics, pharmaceuticals and in many others, not only because they are easily available and are cheaper but also an important reason has been the notion that they are safer than synthetic products, which may not always be true. There are several phytochemicals which beyond a certain limit, diminishes the market potential of products such as phenylpropanoids rich essential oils which get deteriorated specifically by few isomeric forms of phenylpropenes (Miller, E. C.; Swanson, A. B.; Phillips, D. H.; Fletcher, T. L.; Liem, A. and Miller, J. A., Cancer Research, 43 (3), 1124-1134 (1983); Kim; S. C.; Liem; A.; Stewart; B. C. and Miller, J. A. Carcinogensis, 20 (7), 1303-1307 (1999) and Lazutka, J. R.; Mierauskiene, S. and Dedonyte, V. Food and Chemical Technology, 39, 485-492 (2001)). In fact, phenylpropenes are naturally occurring phenolic compounds wherein an aromatic ring is attached to three-carbon side chain (C6-C3 unit), exist either as pair of cis/trans (i.e. xcex1/xcex2-isomer) propenyls or allyl propenes (i.e. xcex3-isomer). Generally, trans-isomers (e.g. xcex1-asarone and isoeugenol etc) are found safer for human consumption while cis/allyl-isomers (e.g. xcex2-asarone and saffrole) are found toxic and carcinogenic (Harborne, J. B. and Baxter, H., Phytochemical Dictionary: A Handbook of Bioactive Compounds from Plants, Taylor and Francis Ltd., Washington D.C., 474 (1993)). The concentration of phenylpropenes and their isomeric ratio in essential oils is greatly affected by growth stages and habitat of the plant, which in turn affect the demand and application of particular oil. Due to this, the most affected oil is calamus oil obtained by steam distillation of rhizomes of Acorus calamus (family: Araceae) which grows wildly and also cultivated in many countries due to its varied medicinal properties and great demand of its essential oil in flavour and perfumery industries (Treben, M., Health Through God""s Pharmacy, Wilhelm Ennthaler, Steyer, Austria, 12-14 (1986); Akhtar, H.; Virmani, O. P.; Popli, S. P.; Misra, L. N.; Gupta, M. M.; Srivastava, G. N.; Abraham, Z. and Singh, A. K., Dictionary of Indian Medicinal Plants, CIMAP, RSM Nagar, Lucknow, 10-11 (1992); Motley, T. J., Economic Botany, 48, 397-412 (1994) and Lawrence, B. M. and Reynolds, R. J., Perfumer and Flavorist 22 (2), 59-67 (1997)). However, a lot of discrepancy and variability in quality of calamus oil has been observed in which tetraploid and hexaploid varieties (distributed extensively in Asian countries like India, Japan, Pakistan and China) contains a very high percentage of toxic xcex2-asarone (varying from 70 to 90%) while diploid and triploid varieties contain limited amount of xcex2-asarone (3 to 8%) which are allowed for use in flavor, perfumery and pharmaceutical industries (Stahl, E. and Keller, K., Planta Medica 43, 128-140 (1981); Waltraud, G. and Schimmer, O., Mutation Research 121, 191-194 (1983); Mazza, G., J. of Chromatography, 328, 179-206 (1985); Nigam, M. C.; Ateeque, A.; Misra, L. N. and Ahmad, A., Indian Perfumer, 34, 282-285 (1990) and Bonaccorsi, I.; Cortroneo, A.; Chowdhury, J. U. and Yusuf, M., Essenze Derv. Agrum., 67(4), 392-402 (1997)).
xcex2-asarone is experimentally proved to be carcinogenic in animals and has also been found to induce tumors in the duodenal region after oral administration. In addition, xcex2-asarone has also shown chromosome damaging effect on human lymphocytes in-vitro after metabolic activation (Taylor, J. M.; Jones, W. I.; Hogan, E. C.; Gross, M. A.; David, D. A. and Cook, E. L., Toxicol. Appl. Pharmacol., 10, 405 (1967); Keller, K.; Odenthal, K. P. and Leng, P. E., Planta Medica 1, 6-9 (1985); Abel, G., Planta Medica, 53(3), 251-253 (1987) and Riaz, M.; Shadab, Q.; Chaudhary, F. M., Hamdard Medicus, 38(2), 50-62 (1995)). As a result, the calamus oil of Asian origin is internationally banned for any kind of use in flavor, perfumery and pharmaceutical industries. To the best of our knowledge, there is no report in which toxic xcex2-asarone of calamus oil is utilized for its value addition except very recently by our group (Sinha, A. K.; Dogra, R. and Joshi, B. P., Ind. J. Chem., 41B, (2002) (in press); Sinha, A. K.; Joshi, B. P. and Dogra, R., Nat. Prod. Lett., 15(6), 439-444 (2001); Sinha, A. K.; Acharya, R. and Joshi, B. P., J. Nat. Prod. (2002) (in press), Sinha, A. K.; Dogra, R. and Joshi, B. P., Sinha, A. K.; Joshi, B. P., and Dogra, R., JP Patent No. 2001.68716 filed on Mar. 12, 2001; Sinha, A. K.; Joshi, B. P., and Dogra, R., U.S. patent application Ser. No. 09/805,832 filed on Mar. 14, 2001; U.S. patent application Ser. No. 09/823,123 filed on Mar. 31, 2001 and Sinha, A. K.; Joshi, B. P., and Dogra, R., PCT/IN 01/00104 filed on May 21, 2001) wherein ammonium formate/palladium-on-charcoal or H2/palladium-on-charcoal assisted reduction of crude calamus oil containing high percentage of toxic xcex2-asarone provides 2,4,5-trimethoxyphenylpropane (dihydro asarone) in 97% purity with yield ranging from 81-87% based on asarones content in calamus oil (Example I). Thus, obtained 2,4,5-trimethoxyphenylpropane (also known as 1-propyl-2,4,5-trimethoxybenzene) is invented for the first time as five times less toxic than xcex2-asarone and thus, this 2,4,5-trimethoxyphenylpropane enables its application in the products such as mouthwashes, tooth pastes, antiseptic soap products, chewing gum flavors and little in spicy products due to its sweet, ylang, slightly spicy and fruity aroma. In addition, 2,4,5-trimethoxyphenylpropane is also discovered as a simple and an economical starting material for synthesis of a salicylamide based antipsychotic drug (5,6-dimethoxy-N[(1-ethyl-2-pyrrolidinyl)methyl]-3-propylsalicylamide) (Thomas, H.; Stefan, B.; Tomas, D. P.; Lars, J.; Peter, S.; Hakan, H. and Orgen, S. O., J. Med. Chem., 33, 1155-1163 (1990) and Sinha, A. K., U.S. patent application Ser. No. 09/652,376 filed on Aug. 31, 2000). In the present invention, we have extended the scope of further exploitation of 2,4,5-trimethoxyphenylpropane of the formula I as simple and economical starting material towards the formation of pharmacological active xcex1-asarone of the formula II.
xcex1-asarone (trans-2,4,5-trimethoxyphenyl-1-propene) is well known for its several pharmacological activities including hypolipideamic and antiplatelet activity but is generally present in traces with xcex2 and xcex3-asarone in various plant species including A. calamus (Patra, A. and Mitra, A. K., J. Nat. Prod., 44, 668-669 (1981); Dung, N. X.; Moi, L. D.; Nam, V. V.; Cu, L. D. and Leclercq, P. A., J. of Ess. Oil Res., 7 (1), 111-112 (1995) and Parmar, V. S.; Jain, S. C.; Bisht, K. S.; Jain, R.; Taneja, P.; Jha, A.; Tyagi, O. D.; Prasad, A. K.; Wengel, J.; Olsen, C. E.; Boll, P. M., Phytochemistry, 46 (4), 597-673 (1997)). Separation of less abundant xcex1-asarone is particularly difficult via column chromatography of asarones rich essential oil. Although, few methods are found in literature for the synthesis of xcex1-asarone including alkaline isomerisation of xcex3-asarone (2,4,5-trimethoxyallylbenzene), however, a little amount of toxic xcex2-asarone is always present with xcex1-asarone during alkaline isomerization (Devgan, O. N. and Bokadia, M. M., Aust. J. Chem., 21, 3001-3003 (1968)). Thus, the reported synthetic methods are not free from drawbacks such as multisteps approach, expensive reagents and overall poor yield with contamination of its isomers. In view of these problems two factors are pivotal for the synthesis of xcex1-asarone, first to achieve highest selectivity for the formation of xcex1-isomer without any presence of other isomers and secondly, search for simple, economical and efficient methods to obtain xcex1-asarone which can be easily achieved by dehydrogenation of 2,4,5-trimethoxyphenylpropane with the help of dehydrogenating reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Among dehydrogenating agents namely, manganese dioxide, p-chloranil, selenium dioxide, Pd/C, selenium and sulphur, DDQ is invented as a single reagent of choice towards formation of xcex1-asarone in a single step by just varying reaction time, temperature, solvent and amount of reagent (DDQ) with or without a solid support such as silica gel, alumina and the like in a mono or biphasic system. In anhydrous solvents namely, alcohol such as methanol, ethanol and the like; aliphatic and aromatic hydrocarbons such as hexane, benzene, toluene and the like; ether such as tetrahydrofuran, dioxane and the like, the reaction between 2,4,5-trimethoxyphenylpropane and varying amount of DDQ, preferably ranging from 1.0 to 1.1 moles, furnishes the corresponding dehydrogenated product i.e. trans-asarone (xcex1-asarone) in 41-44% yield and unreacted starting material (i.e. 2,4,5-trimethoxyphenylpropane) along with yellow coloured compound as a side product (4-6%) while 2,4,5-trimethoxyphenylpropane and varying amount of DDQ, preferably ranging from 1.1 to 1.3 moles, furnishes xcex1-asarone (48-51%) as well as above yellow coloured compound (9-11%) but without any starting material (Example II). It is interesting to note that the addition of a catalytic amount of solid support such celite, silica gel, alumina, resin and the like to the above mixtures of 2,4,5-trimethoxyphenylpropane and DDQ (1.1 to 1.3 moles) dramatically accelerates the rate of dehydrogenation as well as increases the yield of xcex1-asarone (67-72%) (Example III). On the basis of IR, NMR, Mass spectral data, yellow solid is found to be trans-2,4,5-trimethoxycinnamaldehyde which was further confirmed by comparing the mixed m.p. (139-140xc2x0 C.) of standard trans-2,4,5-trimethoxycinnamaldehyde prepared by reaction of xcex1-asarone (trans-asarone, procured from Sigma Chemical Ltd.) with DDQ in dioxane. Further, trans-2,4,5-trimethoxycinnamaldehyde has appeared as a rare phenylpropanoid present in Caesulia axillaries and Alpinia flabella (0.000015%) in traces (Kulkarni, M. M.; Sohoni, J.; Rojatkar, S. R. and Nagasampagi, B. A., Ind. J. Chem. Sec. B 25B, 981-982 (1986) and Kikuzaki, H.; Tesaki, S.; Yonemori, S. and Nakatani, N. Phytochemistry, 56(1), 109-114 (2001), thus, preparation of trans-2,4,5-trimethoxycinnamaldehyde in sufficient quantity opens new vistas for the evaluation of its various applications known for structurally similar cinnamaldehyde derivatives (Tomoshi, K. and Makoto, F., JP Pat. No. 58055414A2; Saotome, K., JP Pat. No. 58201703A2; Watanabe, T., Komeno, T. and Hatanaka, M., JP Pat. No. 6312916A2 and Castelijns, A. M. C. F., Hogeweg, J. M. and vanNispen, S. P. J. M., U.S. Pat. No. 5,811,588)). After having confirmed the structure of xcex1-asarone and trans-2,4,5-trimethoxycinnamaldehyde, our attention was focused towards exclusive formation of xcex1-asarone in high yield without any starting material and yellow side product (i.e. 2,4,5-trimethoxycinnamaldehyde).
An alternate route for the synthesis of xcex1-asarone is appeared via 1-(2,4,5-trimethoxy)phenyl-1-propanone which can be easily prepared by treating 2,4,5-trimethoxyphenylpropane with varying amount of DDQ (1.0 to 3 moles), preferably ranging from 1.6 to 2.1 moles, in an aqueous organic solvent selected from methanol, ethanol, tetrahydrofuran, dioxane and the like. Later on, 2,4,5-trimethoxypropiophenone (isoacoramone) is realized as an interesting rare phenylpropanoid occurring in well known medicinal plant Acorus calamus, Piper marginatum as well as in Acorus tararinowii but only in traces (Mazza, G., J. of Chromatography, 328,179-206 (1985); Santos, B. V. de O. and Chaves, M. C. de O., Biochem. Systematics Ecology, 25, 539-541 (1999) and Jinfeng, Hu and Xiaozhang, Feng, Planta Medica, 66, 662-664 (2000). Thus, formation of 2,4,5-trimethoxypropiophenone (isoacoramone) not only appeared as a synthon for the preparation of xcex1-asarone but also facilitate its more rigorous biological evaluation known for structurally similar propiophenone derivatives (Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S. and Katzenellenbogen, J. A., J. Med. Chem., 43, 4934-4947 (2000) and Jaimol, T.; Moreau, P.; Finiels, A.; Ramaswamy, A. V. and Singh, A. P., Applied Catalysis A: General, 214, 1-10 (2001)). To obtain a xcex1-asarone, 1-(2,4,5-trimethoxy)phenyl-1-propanone is reduced with sodium borohydride into (1-(2,4,5-trimethoxy)phenyl-1-hydroxypropane) followed by acidic dehydration using either p-toluenesulphonic acid or thionyl chloride/pyridine and the like (Example IV-VI).
In conclusion, our invention discloses a simple and economical process for the preparation of pharmacologically active xcex1-asarone along with two important naturally occurring phenylpropanoids namely 2,4,5-trimethoxypropiophenone (isoacaromone) and 2,4,5-trimethoxycinnamaldehyde, starting from relatively cheaper and economical material 2,4,5-trimethoxyphenylpropane obtained via hydrogenation of xcex2-asarone rich Acorus calamus oil as outlined in Scheme-I. Other objectives and advantages of the present invention will be made apparent as the description progresses. 
The main object of the present invention is to prepare pharmacologically active xcex1-asarone from 2,4,5-trimethoxyphenylpropane which is, in fact, is a hydrogenated product of toxic xcex2-asarone isolated from commercially available Acorus calamus oil.
Another object of the present invention is to explore the possibilities of utilizing toxic calamus oil of tetraploid or hexaploid varieties (distributed extensively in Asian countries), thereby, enhancing the profitable use thereof.
Still another object of the invention is to develop a simple process for the preparation of xcex1-asarone exclusively without any contamination of other isomeric forms of asarone (i.e. xcex2 and/or xcex3-isomer).
Yet another object of the invention is to develop a process for the preparation of a non-toxic compound i.e. xcex1-asarone from toxic compound i.e. xcex2-asarone.
Yet another object of the invention is to study the interaction of 2,4,5-trimethoxyphenylpropane by varying time, temperature, solvents and amount of dehydrogenating reagent DDQ.
Yet another object of the invention is to use DDQ as a dehydrogenating reagent for the first time for the preparation of xcex1-asarone exclusively from 2,4,5-trimethoxyphenylpropane.
Yet another object of the invention is to develop easy purification process to obtain xcex1-asarone in high purity as well as in good yield.
Yet another object of the invention is to characterize the unexpected formation of polar yellow solid, which, in fact, formed as a side product along with xcex1-asarone.
Yet another object of the invention is to establish the structure of yellow solid which finally appeared to be a naturally occurring rare trans-2,4,5-trimethoxycinnamaldehyde.
Yet another object of the invention is to develop another route for the preparation of xcex1-asarone starting from 1-(2,4,5-trimethoxy)phenyl-1-propanone.
Yet another object of the invention is to prepare 1-(2,4,5-trimethoxy)phenyl-1-propanone (isoacoramone) by treating 2,4,5-trimethoxyphenylpropane with DDQ in aqueous organic solvent.
Yet another object of the invention is to prepare xcex1-asarone exclusively via reduction of 1-(2,4,5-trimethoxy)phenyl-1-propanone into corresponding 1-(2,4,5-trimethoxy)phenyl-1-propanol followed by the acidic dehydration.
The present invention provides a process for the preparation of pharmacologically active natural occurring xcex1-asarone utilizing combination of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as mild and efficient dehydrogenating agent and 2,4,5-trimethoxyphenylpropane which is, in fact, the hydrogenated product of toxic xcex2-asarone isolated from commercially available calamus oil. It is worthwhile to mention that the above DDQ assisted dehydrogenation process not only led to xcex1-asarone but also provided two more products which later on were characterized as naturally occurring rarer phenylpropanoids namely 2,4,5-trimethocyphenylpropanone (isoacoramone) and 2,4,5-trimethoxycinnamaldehyde. Therefore, formation of xcex1-asarone, isoacoramone and 2,4,5-trimethoxycinnamaldehyde in one step process via DDQ assisted dehydrogenation/oxidation of 2,4,5-trimethoxyphenylpropane, is a cheaper and economical method than so far reported methods, as well as, our invention is capable of forming a series of biologically active phenylpropanoids derivatives.